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Molecular pathways of motor neuron injury.pdf

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• Published: November 2011

Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis

• Laura Ferraiuolo, 
• Janine Kirby, 
• Andrew J. Grierson, 
• Michael Sendtner & 
• Pamela J. Shaw 

Nature Reviews Neurology volume 7, pages616–630 (2011)Cite this article

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Abstract

Amyotrophic lateral sclerosis (ALS) is a genetically diverse disease. At least 15 ALS-associated gene loci have so far been identified, and the causative gene is known in approximately 30% of familial ALS cases. Less is known about the factors underlying the sporadic form of the disease. The molecular mechanisms of motor neuron degeneration are best understood in the subtype of disease caused by mutations in superoxide dismutase 1, with a current consensus that motor neuron injury is caused by a complex interplay between multiple pathogenic processes. A key recent finding is that mutated TAR DNA-binding protein 43 is a major constituent of the ubiquitinated protein inclusions in ALS, providing a possible link between the genetic mutation and the cellular pathology.

근위축성 측삭 경화증(ALS)은 유전적으로 다양한 질병입니다. 지금까지 최소 15개의 루게릭병 관련 유전자 좌위가 확인되었으며, 가족성 루게릭병 사례의 약 30%에서 원인 유전자가 알려져 있습니다. 산발적인 형태의 루게릭병의 기저 요인에 대해서는 알려진 바가 적습니다. 운동 신경세포 변성의 분자 메커니즘은 슈퍼옥사이드 디스뮤타아제 1의 돌연변이로 인한 질환의 하위 유형에서 가장 잘 이해되고 있으며, 현재 운동 신경세포 손상은 여러 병원성 과정 간의 복잡한 상호 작용으로 인해 발생한다는 데 의견이 일치하고 있습니다. 최근의 주요 발견은 돌연변이된 TAR DNA 결합 단백질 43이 루게릭병의 유비퀴틴화 단백질 내포물의 주요 구성 요소이며, 유전적 돌연변이와 세포 병리 사이의 가능한 연결 고리를 제공한다는 것입니다. 

New insights have also indicated the importance of dysregulated glial cell–motor neuron crosstalk, and have highlighted the vulnerability of the distal axonal compartment early in the disease course. In addition, recent studies have suggested that disordered RNA processing is likely to represent a major contributing factor to motor neuron disease. Ongoing research on the cellular pathways highlighted in this Review is predicted to open the door to new therapeutic interventions to slow disease progression in ALS.

또한 새로운 통찰력을 통해 조절 장애가 있는 아교세포-운동 뉴런 crosstalk의 중요성이 밝혀졌으며, 질병 진행 초기에 원위 축삭 구획의 취약성이 강조되었습니다. 또한, 최근 연구에 따르면 무질서한 RNA 처리가 운동 신경 질환의 주요 원인일 가능성이 높다고 합니다. 이 리뷰에서 강조한 세포 경로에 대한 지속적인 연구는 루게릭병의 질병 진행을 늦출 수 있는 새로운 치료적 개입의 문을 열 것으로 예상됩니다.

Key Points

• Multiple cellular events contribute to the pathobiology of amyotrophic lateral sclerosis (ALS), including oxidative stress, mitochondrial dysfunction, excitotoxicity, protein aggregation, impaired axonal transport, neuroinflammation, and dysregulated RNA signaling. 산화 스트레스, 미토콘드리아 기능 장애, 흥분성 독성, 단백질 응집, 축삭 수송 장애, 신경 염증, 조절되지 않는 RNA 신호 등 다양한 세포 사건이 근위축성 측삭 경화증(ALS)의 병태생리학에 기여합니다.

• TAR DNA-binding protein 43 is a major constituent of the ubiquitinated protein inclusions found in surviving motor neurons in most forms of ALS. TAR DNA 결합 단백질 43은 대부분의 루게릭병에서 살아남은 운동 신경세포에서 발견되는 유비퀴틴화 단백질 내포물의 주요 구성 요소입니다.

• Glial pathology and disruption of glial cell–motor neuron communication contribute to neurodegeneration and the propagation of motor neuron injury. 신경교세포 병리 및 신경교세포-운동신경세포 통신 장애는 신경 퇴행과 운동신경세포 손상의 전파에 기여합니다.

• Understanding the links between molecular changes and clinical features of the disease should guide future therapeutic efforts. 루게릭병의 분자적 변화와 임상적 특징 사이의 연관성을 이해하면 향후 치료 노력을 이끌 수 있습니다.

• Degenerative changes in motor neurons seem to affect the health of the distal axonal compartment at an early stage of disease, highlighting an important neuroprotective target. 운동 뉴런의 퇴행성 변화는 질병의 초기 단계에서 원위 축삭 구획의 건강에 영향을 미치는 것으로 보이며 중요한 신경 보호 표적을 강조합니다.